Laser Optoacoustic Imaging System (LOIS) is a novel highly sensitive high resolution digital imaging modality for breast cancer detection utilizing optical tissue contrast and ultrasonic detection of laser-induced acoustic waves. Noninvasive in vivo imaging modalities presently applied for breast cancer detection cannot differentiate benign from malignant lesions. The goal of this project is to develop diagnostic capability for optoacoustic imaging applied in breast cancer detection based on quantitative spectroscopic measurement of hemoglobin oxygenation in tumor angiogenesis. As the system enhancement needed for detection of early tumors with underdeveloped or tumors with suppressed angiogenesis, we propose utilization of nanoparticles absorbing near-infrared laser pulses and conjugated with antibodies that target specifically breast tumor angiogenesis. Our preliminary studies supported by NCI resulted in accomplishment of milestones that documented feasibility and the proof of concept. Optoacoustic contrast between normal tissues and cancerous tumors was shown to be significantly greater (2-6 fold) than contrast provided by conventional modalities. The primary source of this contrast and its variation comes from strong optical absorption in hemoglobin of blood in the tumor angiogenesis. In vivo data supported by medical literature suggest that concentration of oxyhemoglobin in angiogenesis of malignant tumors is substantially reduced relative to that in benign tumors. Pilot studies revealed optimal laser wavelengths in the near-infrared spectral range that can preferentially induce acoustic sources either in malignant tumors (h=760-nm, deoxyhemoglobin) or in benign tumors (h=1064-nm, oxyhemoglobin). Combination of the two optoacoustic images and their ratio will provide differentiation of breast carcinoma from benign fibroadenoma with exceptional sensitivity (owed to high optical contrast) and superior resolution (owed to ultrawide-band piezoelectric detection of resulting ultrasonic waves). Specific aims focus on (1) modification of LOIS to (I) incorporate Nd:YAG laser and Alexandrite lasers into one fiberoptic light delivery system and (ii) construct an advanced bifocal array of ulrawideband ultrasonic transducers for exceptional resolution of two-dimensional images, (2) initial tests using milk-gel phantoms with blood-colored "tumors" resembling optical and mechanical properties of malignant and benign masses, and cysts, (3) evaluation of the LOIS sensitivity and specificity in clinical trials on 24 patients, (4) evaluation of enhancement of sensitivity and specificity of LOIS in mouse model utilizing nanoparticulate contrast agent based on (I) two-orders of magnitude increase in detected signal from nanoparticles hated above the threshold of optoacoustic nonlinearity and (ii) selective accumulation of nanoparticles in breast cancer owed to their conjugation with antibodies against vascular endothelial growth factor.